Wednesday, June 1, 2011

A paper by MIT's own engineer Stephanie Seneff and (as near as I can tell) a couple of medical research-reading renegades was published in the European Journal of Internal Medicine earlier this year. It is remarkable to see (one presumes) a major European biomedical journal publish something from outsiders. More amazing still is the easily understandable, well-referenced and cogent understanding of lipoproteins, metabolism, and brain chemistry. In our specialty journals we often get shallow papers that peck at a single organ system, without a holistic understanding of physiology.

Millions of dollars and several decades have been spent chasing down the most obvious pathology - those plaques and tangles. We innovative humans have invented all sorts of marvelously clever treatments - including vaccines against plaque, and drugs that interfere with plaque synthesis. The problems is the vaccines did no good, and the trials for the plaque-busting drug was halted early due to an obvious "accelerated deterioration in cognition in the treatment group compared to placebo-based controls."

It seems the typical response to such failures is to think - oh, we aren't acting early enough or we aren't busting up enough plaques - which might be the case. Or, as Seneff and crew suggest quite astutely, the amyloid beta proteins that form the plaques might just be there for a good reason, a protective reason, and that's why they cover the Alzheimer's brain with such ferocity.

We know that there is a strong correlation between insulin resistance and early Alzheimer's, and also there is an association between mitochondrial dysfunction (particularly in complex 1) and Alzheimer's. As I discussed in Basic Science: Energy is Everything and Brain Efficiency, when the mitochondria aren't happy, your brain isn't happy. Mitochondrial dysfunction is also implicated in Parkinson's Disease and ALS, both long-term and ultimately fatal degenerative conditions.

And now, a point I've made before (in Low Cholesterol and Suicide)- the brain is relatively small, but has 25% of the body's cholesterol. Cholesterol insulates neurons as part of the myelin sheath and provides the scaffold for the neural network, and is an important part of the membranes and all synapses. While much of the cholesterol used in the brain is made in the brain, there is clear evidence that apolipoprotein E (ApoE) is a big player in the game of shuttling cholesterol, fat, and antioxidants to the central nervous system from the body's main cholesterol factory, the liver. ApoE is made in nerve cells called astrocytes (who tend to and feed neurons), and ApoE allows the astrocytes to suck lipids, antioxidants, and cholesterol arriving in LDL and IDL particles from the bloodstream. Yes, astrocytes can transport LDL across the blood brain barrier.

The biggest genetic risk for Alzheimer's is being a carrier of a certain type of ApoE gene called ApoE4. Research has shown that ApoE4 is associated with reduced cholesterol uptake by the astrocytes. What has been confusing for the lipophobic medical establishment is that ApoE4 is associated with high LDL cholesterol… so it must be that nasty horrible LDL killing the brain! But the key bit to understand is that LDL cholesterol in longitudinal studies tends to drop before the development of Alzheimer's disease. Hmmm. We can't ignore the following tantalizing clue either:

…high cholesterol level is positively correlated with longevity in people over 85 years old, and in some cases has been shown to be associated with better memory function and reduced dementia… the cerebrospinal fluid of [Alzheimer's Disease] patients is substantially depleted in lipoproteins, cholesterol, triglycerides, and free fatty acids compared to matched controls.

All of us, but especially readers of a since-removed blog post that was part of the Venus-gate paleo disruption of a few weeks ago about the supposed dangers of densely packed saturated fat should have an understanding of how lipoproteins work. Lipoproteins (such as HDL, LDL, chylomicrons, and VLDL) basically look like this:

Lipoproteins carry fats and other delicacies through the blood. The blood is dangerous and filled with nasty things like oxygen and iron that can break down our gentle fats. We don't want our fats oxidized - so the lipoproteins tuck the fats into the inside to keep them safe and snuggly. Again, a MAJOR REASON for the particular structure of lipoproteins is to keep those fats safe and not exposed to the blood. Once fats are delivered to cell membranes, we still want to keep them safe - and cholesterol is like a bit of plate armor - it helps the fats stack more tightly, protecting them from oxidative damage and invading microbial pathogens.

Seneff et al continue to stack the evidence in their paper - dietary avoidance of fat (replaced by carbohydrate) and the increasingly zealous prescriptions for cholesterol-lowering medication has coincided with the rise in Alzheimer's Dementia and diabetes and obesity. These are only correlations, but one might consider that to be some evidence in favor of the plausible hypothesis that stripping the brain of cholesterol especially in an oxidative, hyperglycemic environment could lead to very sick neurons.

These sick neurons do their darndest to go forward despite the growing burden of oxidative damage and smokey, spewing mitochondria - until the end, when they are so damaged the only thing to do is to call in the immune system to send self-destruct signals. And here is where those amyloid beta proteins come in - they are hypothesized to try to stand in for cholesterol and to help shift the cell from using the damaged mitochondria to utilizing different sources in the cell cytoplasm to make energy (for the biochem nerds - specifically glucose is redirected to the pentose shunt, an anaerobic pathway generating NADPH which also can protect the cell from oxidation). Their purpose, then, is to reduce the ongoing damage as a last stand prior to self-destruction of the neurons. When the cells ultimately give up the ghost, the defensive forces are left in place, crystallize, and form the famous plaques. As Seneff so elegantly puts it: "A legacy of complex protein debris is left in place."

Back to insulin resistance and hyperglycemia, the legacy in turn of our processed carbohydrate, inflammatory, fructose-intensive Western diets - turns out the same apolipoproteins that are critical to the functioning of our cholesterol machinery are also particularly vulnerable to damage called glycation in a high-glucose environment. Glycation is known to disturb the uptake of ApoE by the astrocytes (that first step in processing cholesterol used by the brain). Diabetics with Apo-E4 are at higher risk for Alzheimer's, and it is thought that the less efficient ApoE4 combined with the detrimental effects of glycation could be the reason.

Enter the ketogenic diet, which in a pilot study has been found to be therapuetic for Alzheimers. It involves an extremely high fat diet, supplying plenty for the brain, and results in the brain being able to use alternative energy sources (ketones) that skip the damaged mitochondrial complex 1. It will also tend to lower insulin resistance and eliminate glycation, as blood sugar will be low.

And then enter the pathogens - with excess glucose and advanced glycolation end-products floating around in the blood, diabetics are more vulnerable to bacterial infection than the average person. Alzheimer's Dementia is also associated with infection with certain chronic pathogens, including H. pylori and Chlamydia pneumoniae. There are plausible mechanisms by which these infections increase inflammation and oxidative damage, hastening the onset of dementia.

What is the scariest scenario? Well, all the diabetics. They are at higher risk for heart disease, and in the US at least they are very aggressively statinized, especially in the last 10 years. It would be considered malpractice for a primary care doc or cardiologist not to encourage statin use in a diabetic with a whiff of high cholesterol. But it seems quite plausible that drastically reducing cholesterol in combination with the hyperglycemia of diabetes is the perfect storm for developing Alzheimer's.

Dr. Steve Parker noted a study that showed no increase in Alzheimer's in autopsies of diabetics. The study was done in Japan between 1998 and 2003, and is strong evidence against the fact that plain old type II diabetes would cause Alzheimer's. In Japan there is, in general, lower cholesterol levels, and in Japanese low cholesterol is known to coincide with stroke risk. In addition, this study was done mostly before the mainstream statin explosion in the United States, anyway. I don't know how aggressively the Japanese diabetics are "treated" for high cholesterol. I wonder if the differences in the processed food burden along with cholesterol-lowering drugs explain the difference between the strong epidemiological evidence linking insulin resistance and diabetes to Alzheimer's in the Western world and the lack of relationship between diabetes and Alzheimer's in the Japanese study.

I see that the triple number shows up here (peer-reviewed, biochem society, 2005, reference #one if you want to delve further..), http://www.biochemsoctrans.cn/bst/033/1087/0331087.pdf

(The basic logic as I understand it, is mostly that as the baby-boomer ages into the late 70s and early 80s the sheer number of people at those ages increases dramatically. This may be mostly an effect in the USA.)

Looks like a theory coming together nicely, only a few kinks to work out.

More possible explanations to why Japanese diabetics might not be as affected. Joel Fuhrman once wrote an article about an old vegan dude who died of Alzheimers, and he attributed it to very low DHA levels (although it could also be low cholesterol) which were measured and were the "lowest I have ever seen" according to Fuhrman. Could DHA, which is abundant in the Japanese diet be a mitigating factor?

Also the Japanese don't tend to be as plagued by massive amounts of linoleic acid. Too much PUFA, especially combined with a high glucose oxidative environment produces advanced lipid peroxidation endproducts, which I can imagine would greatly exacerbate things. That funny man Ray Peat says that a diet plagued by seed oil can be more glycating than sugar alone.

Ketogenic diets definitely protect neurons and supply plenty of cholesterol, I also think that the autophagy they induce could be one more point in their favor.

Mario - yes I totally owe you a thyroid post! Thanks for the links - I have my thyroid textbook now too to be very on top of things.

Stabby - I do think omega 3s are key - they have a lot to do with how the amyloid beta proteins fold in the first place… that's partly why I object to the characterization of Alzheimer's as "type III diabetes - while I do think it contributes, I don't think insulin resistance is the entire story by any means.Agree about autophagy.

Great post! I shared it with my butter-loving husband, who in 1993 was the researcher who made the biochemical discovery of the link between ApoE4 and Alzheimer's Disease, www.ncbi.nlm.nih.gov/pubmed/8446617.

At that time statins were starting to make a splash as a CVD treatment. He remembers thinking at the time, though cholesterol lowering might be beneficial for CVD (he knows otherwise now), it would also negatively impact the development of AD.

It's great to see the research described so clearly and informatively.

Emily, you wrote, " In Japan there is, in general, lower cholesterol levels, and in Japanese low cholesterol is known to coincide with stroke risk." Do you have a citation for this? Sounds correct but would like to distinguish hemorraghic vs. thrombotic strokes as they have different causes/associated factors.Thanks

Thanks Emily. I've been trying to learn more about the dangers of statins - it seems like they're being passed around like candy these days. Your post is illuminating in that regard.

I also want to rationally lower my own risk for CVD. My dad started with heart attacks in his 50's and then was further victimized by the low-fat medical dictum. I remember him spreading hydrogenated vegetable oil spread on his toast in the morning - brilliant medical minds thought up that one for sure.

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About Me

Emily Deans, M.D.: I'm a psychiatrist in Massachusetts searching for evolutionary solutions to the general and mental health problems of the 21st century. Disclaimer: This information is for educational purposes only, and is in no way intended to be personal medical advice. Please ask your physician about any health guidelines seen in this blog, as everyone is different in his or her medical needs.